Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2001-08-07
2004-08-10
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C428S402200, C514S824000
Reexamination Certificate
active
06773719
ABSTRACT:
BACKGROUND OF THE INVENTION
Several human conditions are characterized by distinctive lipid compositions of tissues, cells, membranes, and extracellular regions or structures. For example, in atherosclerosis, cholesterol (unesterified, esterified, and oxidized forms) and other lipids accumulate in cells and in extracellular areas of the arterial wall and elsewhere. These lipids have potentially harmful biologic effects, for example, by changing cellular functions, including gene expression, and by narrowing the vessel lumen, obstructing the flow of blood. Removal of these lipids would provide numerous substantial benefits. Moreover, cells, membranes, tissues, and extracellular structures will benefit in general from compositional alterations that include increasing resistance to oxidation and oxidative damage, such as by increasing the content and types of anti-oxidants, removing oxidized material, and increasing the content of material that is resistant to oxidation. In aging, cells have been shown to accumulate sphingomyelin and cholesterol, which alter cellular functions. These functions can be restored in vitro by removal of these lipids and replacement with phospholipid from liposomes. A major obstacle to performing similar lipid alterations in vivo has been disposition of the lipids mobilized from tissues, cells, extracellular areas, and membranes. Natural (e.g., high-density lipoproteins) and synthetic (e.g., small liposomes) particles that could mobilize peripheral tissue lipids have a substantial disadvantage: they deliver their lipids to the liver in a manner that disturbs hepatic cholesterol homeostasis, resulting in elevations in plasma concentrations of harmful lipoproteins, such as low-density lipoprotein (LDL), a major atherogenic lipoprotein. There exist a need for a better method to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo.
The intravenous administration of cholesterol-poor phospholipid vesicles (liposomes) or other particles that transport cholesterol and other exchangeable material from lipoproteins and peripheral tissues, including atherosclerotic arterial lesions, to the liver produces substantial derangements of hepatic cholesterol homeostasis, such as enhanced hepatic secretion of apolipoprotein-B, and suppression of hepatic LDL receptors. The hepatic derangements lead to increase plasma concentrations of LDL and other atherogenic lipoproteins. Increased concentrations of LDL or other atherogenic lipoproteins will accelerate, not retard, the development of vascular complications. Deranged hepatic cholesterol homeostasis can also be manifested by abnormal regulation of genes, such as a gene for the LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha hydroxylase, and a gene regulating a function involved in cholesterol homeostasis. There exists a need for methods and compounds that can produce a removal of cholesterol and other exchangeable material, from peripheral cells, tissues, organs, and extracellular regions, and that can produce a delivery of material, such as phospholipids, to cells, tissues, or organs, extracellular regions without harmfully disrupting hepatic cholesterol homeostasis and plasma concentrations of atherogenic lipoproteins.
By way of example, atherosclerosis, a major killer in Western countries, is characterized by the accumulation of cholesterol and cholesteryl ester in cells and in extracellular areas of the arterial wall and elsewhere. There exists a need for a better method to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo. There further exists a need for methods or compounds that can produce removal of cholesterol from cellular and extracellular regions of arteries, but without provoking a rise in the plasma concentration of LDL.
The invention described herein provides methods and compositions related to the removal of cholesterol from arteries, whole controlling plasma concentrations of LDL. The present invention addresses these needs so that diseases and detrimental medical conditions can be treated, controlled or eliminated.
This invention provides methods and compositions that relate to the “reverse” transport of lipids and other exchangeable material from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations. There exists a need for a method of, treatment, and a pharmaceutical composition for forcing the reverse transport of lipids from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations; of regulating hepatic parenchymal cell cholesterol content and metabolism in a cell having at least one gene selected from the group consisting of a gene for an LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha-hydroxylase, and a gene regulating a function involved in cholesterol homeostasis; and, homeostasis thereof; suppressing hepatic expression of a cholesterol ester transfer protein gene in vivo, whereby plasma LDL and HDL are controlled as a result of the administration; suppressing the rise in plasma LDL concentrations after administration of an agent having small acceptors of cholesterol or other lipids; of diagnosing a side-effect of reverse transport of cholesterol from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period, whereby a side effect of administration of the liposomes is diagnosed and effectively regulated; and, diagnosing and treating a side-effect of reverse transport of lipids from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period. There further exists a need for a system in which patients will have a decreased risk of developing atherosclerosis and/or cellular changes from aging; an improved method of reducing the lipid content of lesions.
The invention described herein provides methods and compositions related to the removal of cholesterol and other exchangeable material from peripheral tissues, and otherwise altering peripheral tissue lipids, while controlling plasma concentrations of LDL and other atherogenic lipoproteins and avoiding harmful disruptions of hepatic cholesterol homeostasis. Specific genes in both the peripheral tissues and in the liver are controlled by these methods and compositions. There exists a need for better methods to manipulate the lipid content and composition of peripheral tissues, cells, membranes, and extracellular regions in vivo, particularly in regard to diseases and processes involving oxidation and oxidative damage. Moreover, currently available artificial particles for intravenous administration contain significant amounts of oxidized material (Helbock et al. Pediatrics 91:83-87, 1993), which contributes to their unsuitability for these purposes.
There further exists a need for methods or compounds that can produce a removal of cholesterol and other exchangeable material, including oxidized materials, from peripheral cells, tissues, organs, and extracellular regions, and that can produce a delivery of anti-oxidants to cells, tissues, organs, and extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis, including hepatic gene expression and regulation.
The invention described herein provides methods and compositions related to the removal of cholesterol and other exchangeable material from peripheral tissues, and otherwise altering peripheral tissue composition, to reduce or avoid oxidation and its effects and products, while controlling plasma concentrations of LDL and other atherogenic lipoproteins and avoiding harmful disruption of hepatic cholesterol homeostasis. It is an object of the invention of the present invention to solve the problems articulated above and other problems in the art.
Renal failure, both acute and chronic, is a major health problem. Current treatm
Hope Michael J.
Rodrigueza Wendi V.
Williams Kevin Jon
Esperion LUV Development, Inc.
Jones Day
Kishore Gollamudi S.
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